Recovering Hidden Responder Groups in Individuals Receiving Neurofeedback for Tinnitus

The widespread understanding that chronic tinnitus is a heterogeneous phenomenon with various neural oscillatory profiles has spurred investigations into individualized approaches in its treatment. Neurofeedback, as a non-invasive tool for altering neural activity, has become increasingly popular in the personalized treatment of a wide range of neuropsychological disorders. Despite the success of neurofeedback on the group level, the variability in the treatment efficacy on the individual level is high, and evidence from recent studies shows that only a small number of people can effectively modulate the desired aspects of neural activity. To reveal who may be more suitable, and hence benefit most from neurofeedback treatment, we classified individuals into unobserved subgroups with similar oscillatory trajectories during the treatment and investigated how subgroup membership was predicted by a series of characteristics. Growth mixture modeling was used to identify distinct latent subgroups with similar oscillatory trajectories among 50 individuals suffering from chronic subjective tinnitus (38 male, 12 female, mean age = 47.1 ± 12.84) across 15 neurofeedback training sessions. Further, the impact of characteristics and how they predicted the affiliation in the identified subgroups was evaluated by including measures of demographics, tinnitus-specific (Tinnitus Handicap Inventory) and depression variables, as well as subjective quality of life subscales (World Health Organization—Quality of Life Questionnaire), and health-related quality of life subscales (Short Form-36) in a logistic regression analysis. A latent class model could be fitted to the longitudinal data with a high probability of correctly classifying distinct oscillatory patterns into 3 different groups: non-responder (80%), responder (16%), and decliner (4%). Further, our results show that the health-related wellbeing subscale of the Short Form-36 questionnaire was differentially associated with the groups. However, due to the small sample size in the Responder group, we are not able to provide sufficient evidence for a distinct responder profile. Nevertheless, the identification of oscillatory change-rate differences across distinct groups of individuals provides the groundwork from which to tease apart the complex and heterogeneous oscillatory processes underlying tinnitus and the attempts to modify these through neurofeedback. While more research is needed, our results and the analytical approach presented may bring clarity to contradictory past findings in the field of tinnitus research, and eventually influence clinical practice

Accounting for Heterogeneity: Mixed-Effects Models in Resting-State EEG Data in a Sample of Tinnitus Sufferers

In neuroscience, neural oscillations and other features of brain activity recorded by electroencephalography (EEG) are typically statistically assessed on the basis of the study's population mean to identify possible blueprints for healthy subjects, or subjects with diagnosable neurological or psychiatric disorders. Despite some inter-individual similarities, there is reason to believe that a discernible portion of the individual brain activity is subject-specific. In order to encompass the potential individual source of variance in EEG data and psychometric parameters, we introduce an innovative application of linear mixed-effects models (LMM) as an alternative procedure for the analysis of resting-state EEG data. Using LMM, individual differences can be modelled through the assumptions of idiosyncrasy of all responses and dependency among data points (e.g., from the same subject within and across units of time) via random effects parameters. This report provides an example of how LMM can be used for the statistical analysis of resting-state EEG data in a heterogeneous group of subjects; namely, people who suffer from tinnitus (ringing in the ear/s). Results from 49 participants (38 male, mean age of 46.69 ± 12.65 years) revealed that EEG signals were not only associated with specific recording sites, but exhibited regional specific oscillations in conjunction to symptom severity. Tinnitus distress targeted the frequency bands beta3 (23.5-35 Hz) and gamma (35.5-45 Hz) in right frontal regions, whereas delta (0.5-4 Hz) exhibited significant changes in temporal-parietal sources. Further, 57.8% of the total variance in EEG power was subject-specific and acknowledged by the LMM framework and its prediction. Thus, a deeper understanding of both the underlying statistical and physiological patterns of EEG data was gained

Smartphone Apps in the Context of Tinnitus: Systematic Review

Smartphones containing sophisticated high-end hardware and offering high computational capabilities at extremely manageable costs have become mainstream and an integral part of users' lives. Widespread adoption of smartphone devices has encouraged the development of many smartphone applications, resulting in a well-established ecosystem, which is easily discoverable and accessible via respective marketplaces of differing mobile platforms. These smartphone applications are no longer exclusively limited to entertainment purposes but are increasingly established in the scientific and medical field. In the context of tinnitus, the ringing in the ear, these smartphone apps range from relief, management, self-help, all the way to interfacing external sensors to better understand the phenomenon. In this paper, we aim to bring forth the smartphone applications in and around tinnitus. Based on the PRISMA guidelines, we systematically analyze and investigate the current state of smartphone apps, that are directly applied in the context of tinnitus. In particular, we explore Google Scholar, CiteSeerX, Microsoft Academics, Semantic Scholar for the identification of scientific contributions. Additionally, we search and explore Google’s Play and Apple's App Stores to identify relevant smartphone apps and their respective properties. This review work gives (1) an up-to-date overview of existing apps, and (2) lists and discusses scientific literature pertaining to the smartphone apps used within the context of tinnitus

Doctoral Studies as part of an Innovative Training Network (ITN): Early Stage Researcher (ESR) experiences [version 2; peer review: 2 approved]

Background: The Marie-Skłodowska-Curie Actions’ (MSCA) Innovative Training Network (ITN) is a doctoral training programme jointly implemented by academic institutions and industries from countries across Europe and beyond. To our knowledge no study has examined the experience of students participating in MSCA-ITNs. This study aims to evaluate and report MSCA-ITN Early Stage Researcher (ESR) experiences. Methods: The Innovative Training Network - Evaluation Questionnaire (ITN-EQ) was developed to assess supervision, training, collaborations and experiences of ESRs and forwarded to two tinnitus-related ITNs and seven ITNs of other disciplines. Results: Key advantages identified included better career prospects, multidisciplinary research opportunities/collaborations, international exposure, personal/professional development, plus generous salaries and research budgets. However, lack of a common EU framework resulted in the experience being largely dependent on the host institution, country and supervisor. Moreover, managing the dual requirements of ITNs and host institutions while completing a three-year PhD seemed challenging for most ESRs. ESR involvement in workshop and training school planning was desirable. More than 80% of ESRs rated the overall ITN experience favourably and 98.3% would recommend the same to prospective PhD students. Conclusions: This report could provide valuable insights in planning and management of future ITNs and could assist prospective students in their decision of joining an ITN for their PhD

Doctoral Studies as part of an Innovative Training Network (ITN):Early Stage Researcher (ESR) experiences [version 2; peer review: 2 approved]

Background: The Marie-Skłodowska-Curie Actions’ (MSCA) Innovative Training Network (ITN) is a doctoral training programme jointly implemented by academic institutions and industries from countries across Europe and beyond. To our knowledge no study has examined the experience of students participating in MSCA-ITNs. This study aims to evaluate and report MSCA-ITN Early Stage Researcher (ESR) experiences. Methods: The Innovative Training Network - Evaluation Questionnaire (ITN-EQ) was developed to assess supervision, training, collaborations and experiences of ESRs and forwarded to two tinnitus-related ITNs and seven ITNs of other disciplines. Results: Key advantages identified included better career prospects, multidisciplinary research opportunities/collaborations, international exposure, personal/professional development, plus generous salaries and research budgets. However, lack of a common EU framework resulted in the experience being largely dependent on the host institution, country and supervisor. Moreover, managing the dual requirements of ITNs and host institutions while completing a three-year PhD seemed challenging for most ESRs. ESR involvement in workshop and training school planning was desirable. More than 80% of ESRs rated the overall ITN experience favourably and 98.3% would recommend the same to prospective PhD students. Conclusions: This report could provide valuable insights in planning and management of future ITNs and could assist prospective students in their decision of joining an ITN for their PhD

Corrigendum:Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers (Front. Aging Neurosci., (2021), 13, (647285), 10.3389/fnagi.2021.647285)

In the original article, there was an error. For the sentence “NMDA receptor antagonists (AM-101) have been discontinued in phase III for not meeting endpoints (van de Heyning et al., 2014)” there was a typographical error (phase III should have been phase II). In addition, it was brought to our attention that clinical trials for AM-101 are ongoing. A correction has been made to section 6. Treatment Development, Subsection 6.4. Pharmacology-Based Interventions, paragraph 1. The corrected paragraph is below. A wide variety of therapeutic drugs have been used to relieve tinnitus (Elgoyhen and Langguth, 2010). For acute tinnitus, a dose-dependent reduction in tinnitus intensity was observed with intravenous lidocaine (Trellakis et al., 2006). However, its use is controversial due to its short-lasting response, its potentially life threatening arrhythmogenic side effects, and the low bioavailability of its oral form (Israel et al., 1982; Trellakis et al., 2007; Gil-Gouveia and Goadsby, 2009). A potential goal of pharmacologic tinnitus research could be to identify the mechanism by which lidocaine interferes with tinnitus and mimic this effect using a drug with better tolerance that can be orally administered. For chronic tinnitus, the off-label use of medicines like betahistine (Hall et al., 2018d), anticonvulsants (Hoekstra et al., 2011), and glutamate receptor antagonists have shown little or no effect in clinical trials. Prescription of antidepressants and benzodiazepines is limited to tinnitusassociated comorbidities such as depression, insomnia and anxiety (Langguth et al., 2019). Moreover, three clinical research programs, in the last few years, were discontinued in phase II and III. AMPA antagonist selurampanel (BGG492) has not resulted in a new compound (Cederroth et al., 2018). NMDA receptor antagonists (AM-101) did not meet the primary endpoint of improving minimum masking level in acute tinnitus in a phase II clinical trial but showed improvement for tinnitus loudness, annoyance, sleep difficulties, and tinnitus impact in patients with tinnitus after noise trauma or otitis media (van de Heyning et al., 2014). Many other treatments decreasing tinnitus percept or targeting central auditory processing pathways are at a preclinical phase (Schilder et al., 2019). The modulator of voltage-gated potassium channels (Kv3.1) (AUT00063) was not effective in alleviating tinnitus symptoms (Hall et al., 2019b). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated

Standardised profiling for tinnitus research: The European School for Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ)

Background: The heterogeneity of tinnitus is substantial. Its numerous pathophysiological mechanisms and clinical manifestations have hampered fundamental and treatment research significantly. A decade ago, the Tinnitus Research Initiative introduced the Tinnitus Sample Case History Questionnaire, a case history instrument for standardised collection of information about the characteristics of the tinnitus patient. Since then, a number of studies have been published which characterise individuals and groups using data collected with this questionnaire. However, its use has been restricted to a clinical setting and to the evaluation of people with tinnitus only. In addition, it is limited in the ability to capture relevant comorbidities and evaluate their temporal relationship with tinnitus. Method: Here we present a new case history instrument which is comprehensive in scope and can be answered by people with and without tinnitus alike. This ‘European School for Interdisciplinary Tinnitus Research Screening Questionnaire’ (ESIT-SQ) was developed with specific attention to questions about potential risk factors for tinnitus (including demographics, lifestyle, general medical and otological histories), and tinnitus characteristics (including perceptual characteristics, modulating factors, and associations with co-existing conditions). It was first developed in English, then translated into Dutch, German, Italian, Polish, Spanish, and Swedish, thus having broad applicability and supporting international collaboration. Conclusions: With respect to better understanding tinnitus profiles, we anticipate the ESIT-SQ to be a starting point for comprehensive multi-variate analyses of tinnitus. Data collected with the ESIT-SQ can allow establishment of patterns that distinguish tinnitus from non-tinnitus, and definition of common sets of tinnitus characteristics which might be indicated by the presence of otological or comorbid systemic diseases for which tinnitus is a known symptom

Multidisciplinary Tinnitus Research: Challenges and Future Directions from the Perspective of Early Stage Researchers

Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: (1) Further establishment of multicenter and multidisciplinary collaborations; (2) Systematic reviews and syntheses of existing knowledge; (3) Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; (4) The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity

Multidisciplinary Tinnitus Research: Challenges and Future Directions from the Perspective of Early Stage Researchers

Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: (1) Further establishment of multicenter and multidisciplinary collaborations; (2) Systematic reviews and syntheses of existing knowledge; (3) Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; (4) The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity